The present invention is concerned with a novel process for the manufacture of racemic and optically active 3-amino-pyrrolidine derivatives and with the use of this process for the production of cephalosporin derivatives.
3-Amino-pyrrolidine derivatives, especially optically active 3-amino-pyrrolidine derivatives, are important intermediates for the production of agrochemicals and of pharmaceutically active substances such as, for example, of vinylpyrrolidinone-cephalosporin derivatives.
3-Amino-pyrrolidine derivatives can be manufactured in a manner known per se, for example as described in EP-A-0 218 249 starting from 1,2,4-trisubstituted butane derivatives such as e.g. tribromobutane or trihydroxybutane. The racemic derivatives can then, if desired, be converted by a racemate resolution into optically active 3-amino-pyrrolidine derivatives, as described in JP 09124595-A. A process for the manufacture of optically active 3-amino-pyrrolidine derivatives based on the conversion of 4-hydroxy-proline as described, for example, in J. Med. Chem. 1764(92), 35, gives optically active 3-aminopyrrolidine over 3 steps.
The known methods for the manufacture of 3-aminopyrrolidine derivatives as described, for example, in UK Patent No. 1,392,194, EP-A-0 391 169 and U.S. Pat. No. 4,916,141, are time consuming and lead to expensive intermediates. The interest in other processes for the manufacture of 3-amino-pyrrolidine derivatives, especially of optically active 3-amino-pyrrolidine derivatives, is therefore extremely high. Thus, Tomori et al. (Heterocycles, 1997, 1, 213–225) have synthesized (S)-3-(t-butoxycarbonylamino)-pyrrolidine from (S)-3-benzyloxycarbonylamino-1,4-dimethanesulfonyloxybutane by cyclization with excess allylamine and deallylation of the resulting (S)-1-allyl-3-(benzyloxycarbonylamino)pyrrolidine with palladium on charcoal. However, on a technical scale allylamine is unpractical, being a poisonous, inflammable and explosive liquid; also, palladium is an expensive catalyst.
As can be seen, there is a need for a practical, safe, technical scale synthetic method for the synthesis of 3-aminopyrrolidine derivatives. Such a synthetic method should be cost effective and able to be performed safely on a large scale.